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Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age.

Chakravarthy MV, Zhu Y, Wice MB, Coleman T, Pappan KL, Marshall CA, McDaniel ML, Semenkovich CF - Diabetes (2008)

Bottom Line: Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet.Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate beta-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic beta-cell to establish a template for hyperfunction in early life and beta-cell failure with age.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA.

ABSTRACT

Objective: Low birth weight is associated with diabetes in adult life. Accelerated or "catch-up" postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.

Research design and methods: We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age.

Results: FASDEL mice did not manifest catch-up growth or insulin resistance. beta-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but beta-cell failure and diabetes occurred with age. FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because beta-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized beta-cell mass in utero.

Conclusions: Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate beta-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic beta-cell to establish a template for hyperfunction in early life and beta-cell failure with age.

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Increased fetal β-cell mass in an FAS-independent model of intrauterine growth restriction. A: Transgenic overexpression of UCP-1 in skeletal muscle (UCP-Tg), confirmed by Western blotting using UCP-1 antibody (top panel), leads to intrauterine growth restriction at E18.5 (bottom panel). BAT, brown adipose tissue. WT, wild type. B and C: UCP-Tg fetuses have decreased body weight (B) and length (C). WT, wild type. D: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (× 10 magnification). WT, wild type. E and F: Islet area (E) and total β-cell mass (F). WT, wild type. G and H: Replication of β-cells assayed by PCNA and insulin double immunostaining (G) and apoptosis assayed by cleaved caspase-3 and insulin double immunostaining (H) from pancreatic sections of E18.5 wild-type (WT) and UCP-Tg fetuses. All results are means ± SE of 10–12 mice per group. *P < 0.05 compared vs. the corresponding wild-type mice. I: Model for the developmental programming of pancreatic β-cells. β-Cells respond to intrauterine body size by modulating insulin secretion. Early hypersecretion of insulin likely represents an adaptation to allow optimal fetal growth. However, this early increase entrains β-cell failure with age leading to diabetes. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
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f7: Increased fetal β-cell mass in an FAS-independent model of intrauterine growth restriction. A: Transgenic overexpression of UCP-1 in skeletal muscle (UCP-Tg), confirmed by Western blotting using UCP-1 antibody (top panel), leads to intrauterine growth restriction at E18.5 (bottom panel). BAT, brown adipose tissue. WT, wild type. B and C: UCP-Tg fetuses have decreased body weight (B) and length (C). WT, wild type. D: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (× 10 magnification). WT, wild type. E and F: Islet area (E) and total β-cell mass (F). WT, wild type. G and H: Replication of β-cells assayed by PCNA and insulin double immunostaining (G) and apoptosis assayed by cleaved caspase-3 and insulin double immunostaining (H) from pancreatic sections of E18.5 wild-type (WT) and UCP-Tg fetuses. All results are means ± SE of 10–12 mice per group. *P < 0.05 compared vs. the corresponding wild-type mice. I: Model for the developmental programming of pancreatic β-cells. β-Cells respond to intrauterine body size by modulating insulin secretion. Early hypersecretion of insulin likely represents an adaptation to allow optimal fetal growth. However, this early increase entrains β-cell failure with age leading to diabetes. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)

Mentions: The association between fetal body size and fetal β-cell mass was also confirmed in a different model of intrauterine growth restriction, mice with ectopic expression of UCP-1 in skeletal muscle (25,26) (Fig. 7A, top). Decreased body size (Fig. 7A–C) persists and peripheral insulin sensitivity is increased in these mice (26). Islet area and β-cell mass in E18.5 UCP-1 fetuses from >10 litters were inversely associated with intrauterine body size (Fig. 7D–F) (online appendix Fig. 1B). Increased β-cell mass was due to a combination of increased β-cell proliferation and decreased apoptosis (Fig. 7G and H).


Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age.

Chakravarthy MV, Zhu Y, Wice MB, Coleman T, Pappan KL, Marshall CA, McDaniel ML, Semenkovich CF - Diabetes (2008)

Increased fetal β-cell mass in an FAS-independent model of intrauterine growth restriction. A: Transgenic overexpression of UCP-1 in skeletal muscle (UCP-Tg), confirmed by Western blotting using UCP-1 antibody (top panel), leads to intrauterine growth restriction at E18.5 (bottom panel). BAT, brown adipose tissue. WT, wild type. B and C: UCP-Tg fetuses have decreased body weight (B) and length (C). WT, wild type. D: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (× 10 magnification). WT, wild type. E and F: Islet area (E) and total β-cell mass (F). WT, wild type. G and H: Replication of β-cells assayed by PCNA and insulin double immunostaining (G) and apoptosis assayed by cleaved caspase-3 and insulin double immunostaining (H) from pancreatic sections of E18.5 wild-type (WT) and UCP-Tg fetuses. All results are means ± SE of 10–12 mice per group. *P < 0.05 compared vs. the corresponding wild-type mice. I: Model for the developmental programming of pancreatic β-cells. β-Cells respond to intrauterine body size by modulating insulin secretion. Early hypersecretion of insulin likely represents an adaptation to allow optimal fetal growth. However, this early increase entrains β-cell failure with age leading to diabetes. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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f7: Increased fetal β-cell mass in an FAS-independent model of intrauterine growth restriction. A: Transgenic overexpression of UCP-1 in skeletal muscle (UCP-Tg), confirmed by Western blotting using UCP-1 antibody (top panel), leads to intrauterine growth restriction at E18.5 (bottom panel). BAT, brown adipose tissue. WT, wild type. B and C: UCP-Tg fetuses have decreased body weight (B) and length (C). WT, wild type. D: Representative pancreatic sections immunostained with anti-insulin antibody. The arrows depict insulin-positive areas within each islet surrounded by normal pancreatic acinar cells (× 10 magnification). WT, wild type. E and F: Islet area (E) and total β-cell mass (F). WT, wild type. G and H: Replication of β-cells assayed by PCNA and insulin double immunostaining (G) and apoptosis assayed by cleaved caspase-3 and insulin double immunostaining (H) from pancreatic sections of E18.5 wild-type (WT) and UCP-Tg fetuses. All results are means ± SE of 10–12 mice per group. *P < 0.05 compared vs. the corresponding wild-type mice. I: Model for the developmental programming of pancreatic β-cells. β-Cells respond to intrauterine body size by modulating insulin secretion. Early hypersecretion of insulin likely represents an adaptation to allow optimal fetal growth. However, this early increase entrains β-cell failure with age leading to diabetes. (Please see http://dx.doi.org/10.2337/db08-0404 for a high-quality digital representation of this image.)
Mentions: The association between fetal body size and fetal β-cell mass was also confirmed in a different model of intrauterine growth restriction, mice with ectopic expression of UCP-1 in skeletal muscle (25,26) (Fig. 7A, top). Decreased body size (Fig. 7A–C) persists and peripheral insulin sensitivity is increased in these mice (26). Islet area and β-cell mass in E18.5 UCP-1 fetuses from >10 litters were inversely associated with intrauterine body size (Fig. 7D–F) (online appendix Fig. 1B). Increased β-cell mass was due to a combination of increased β-cell proliferation and decreased apoptosis (Fig. 7G and H).

Bottom Line: Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet.Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate beta-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic beta-cell to establish a template for hyperfunction in early life and beta-cell failure with age.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, Missouri, USA.

ABSTRACT

Objective: Low birth weight is associated with diabetes in adult life. Accelerated or "catch-up" postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine beta-cell-specific programming or by altered metabolism associated with catch-up growth is unknown.

Research design and methods: We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age.

Results: FASDEL mice did not manifest catch-up growth or insulin resistance. beta-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but beta-cell failure and diabetes occurred with age. FASDEL beta-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because beta-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized beta-cell mass in utero.

Conclusions: Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate beta-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic beta-cell to establish a template for hyperfunction in early life and beta-cell failure with age.

Show MeSH
Related in: MedlinePlus